In general, a central nervous mechanism which maintains and controls consciousness is composed of two systems, i.e., ascending midbrain reticular formation activating system and hypothalamus activating system. That is, brainstem reticular body and hypothalamus, as well as hemicerebrum and thalamus which are affected by them, are related to consciousness. Disturbance of consciousness occurs when the functions of these organs are impaired by an impact on head (neurotrauma) or cerebral ischemia. Agents for relieving disturbance of consciousness act on central nervous systems concerned with consciousness, to exhibit a relieving effect. As such agents for relieving disturbance of consciousness, there have been known thyrotropin releasing hormone tartrate (hereinafter referred to as TRH), meclofenoxate hydrochloride, CDP-choline, etc.
The ascending midbrain reticular formation activating system participates greatly in a central nervous mechanism which controls sleep. Anesthesia by use of pentobarbital or the like is induction of sleep by inhibition of the aforesaid activating system. Narcotic antagonists act on the inhibited ascending midbrain reticular formation activating system to recover the function of the system. As the narcotic antagonists, there have been known methamphetamine hydrochloride, doxapram hydrochloride, TRH, etc. The above-mentioned conventional agents for relieving disturbance of consciousness and narcotic antagonists, however, are all different from apovincaminic acid skeleton.
On the other hand, VA-045 is a compound disclosed in Japanese Patent KOKAI No. 2-167279, and it has an excellent curative effect on cerebral ischemia, hypertension and the like because of its cerebro-vasodilation effect. However, of apovincaminic acid derivatives including this compound, none is known to have relieving effect on disturbance of consciousness or antagonistic effect on narcotism.
By the way, cerebro-vasodilators improve cerebral circulation by relaxation of cerebral smooth muscle, and drugs heretofore known as cerebro-vasodilators (e.g. vinpocetine, nifedipine, nicardipine verapamil) do not have relieving effect on disturbance of consciousness or antagonistic effect on narcotism.
An object of the present invention is to provide an agent for relieving disturbance of consciousness and a narcotic antagonist which are novel.